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Current Controlled Trials in Cardiovascular Medicine
December 2001 Vol 2 No 6
Krakoff
Commentary
Comments on ALLHAT and doxazosin
Lawrence R Krakoff
Englewood Hospital and Medical Center, Englewood, New Jersey, USA
Correspondence: Lawrence R Krakoff, [email protected]
Published online: 1 November 2001
Curr Control Trials Cardiovasc Med 2001, 2:254-256
© 2001 BioMed Central Ltd (Print ISSN 1468-6708; Online 1468-6694)
Abstract
This commentary has two purposes: to summarize the rationale, design and initial results of the
Antihypertensive and Lipid Lowering Treatment to Prevent Heart Attack Trial (ALLHAT) trial; and to
provide a history of the response to ALLHAT that led to a civil action and a Citizens Petition that was the
basis for a public hearing by the US Food and Drug Administration, in May 2001. The author concludes
that the results of ALLHAT should be widely disseminated. All clinicians must be warned that initial
therapy with doxazosin (and possibly other alpha1 blockers) is definitely inferior to low dose diuretic
treatment for patients at high risk for cardiovascular disease, such as those enrolled in ALLHAT.
Keywords clinical trial, diuretic, doxazosin, heart failure, hypertension
In April 2000, the first results of the Antihypertensive and
Lipid Lowering Treatment to Prevent Heart Attack Trial
(ALLHAT) were published summarizing the comparison
between two of the four drugs studied (chlorthalidone and
doxazosin) as initial monotherapy for hypertension [1]. This
prospective, randomized trial was designed to compare a
diuretic (chlorthalidone) with long-acting (once-a-day) drugs
among different classes: angiotensin-converting enzyme
inhibitor (lisinopril); calcium-channel blocker (amlodipine);
and alpha blocker (doxazosin). The diuretic had been the
mainstay of several previous trials, particularly the Systolic
Hypertension in the Elderly Program (SHEP) study [2].
During the first three years of the trial, the Data Safety and
Monitoring Committee became aware of different event rates
between two groups and, after considerable deliberation,
made the decision to discontinue the arm assigned to
doxazosin for two stated reasons. One reason was an
extremely low likelihood that doxazosin would prove superior
to chlorthalidone when the study would be completed as
planned. The second reason was a pattern of increased
morbid events in comparing doxazosin to the diuretic, which
was highly significant on statistical analysis. This pattern is
shown in Table 1. While event rates for fatal cardiovascular
disease were similar, there was a disturbing tendency for
stroke and a definite trend for heart failure to occur more
often in the doxazosin group, than in the group taking
chlorthalidone. For heart failure, the curves for event rates
diverged quite early in the trial, within the first year, but
continued to separate over the three-year period of analysis.
ALLHAT continues with ongoing comparisons for amlodipine,
lisinopril, and chlorthalidone.
The results of ALLHAT regarding doxazosin were first made
public by a presentation at the meeting of the American
College of Cardiology, March 2000, and the subsequent
publication. Several news agencies published reports of the
study, and comments appeared in a few medical journals.
There was, however, no action taken by either the United
States Food and Drug Administration (FDA) or the Joint
National Committee on Prevention, Detection, Evaluation,
and Treatment of High Blood Pressure, which authored the
most recent advisory guideline for the National Heart Lung
and Blood Institute [3]. In May 2001, however, after initiation
of a class action lawsuit and a Citizens Petition, the FDA held
a hearing on the issue. Sidney Wolfe and the author gave
presentations recommending that all physicians receive a
warning with an interpretation of the ALLHAT results, and
FDA = United States Food and Drug Administration.
ALLHAT = Antihypertensive and Lipid Lowering Treatment to Prevent Heart Attack Trial; HOPE = Heart Outcomes Prevention Evaluation; SHEP =
Systolic Hypertension in the Elderly Program.
Available online http://cvm.controlled-trials.com/content/2/6/254
that the labeling and indications for doxazosin be changed by
Pfizer, the company which developed and markets doxazosin
as Cardura®. Pfizer’s representatives argued that doxazosin
is a safe and effective antihypertensive drug, based on their
own accumulated studies, with no need for any additional
warning or change in labeling. The remainder of this article
will summarize the basis for a warning and address the
arguments of those who conclude that nothing further needs
to be done.
Table 1
Current treatment of hypertension
There is no longer any doubt that treatment of hypertension is
beneficial and prevents stroke, coronary heart disease, and
congestive heart failure. This is particularly so for high-risk
populations, such as those over 50 years of age, with other
risk factors and target organ damage. For the past 20 years,
the proliferation of new antihypertensive drug classes has led
to speculation (based on various kinds of evidence) that for
equal reduction of blood pressure, some classes might be
more beneficial than others with regard to effectiveness in
preventing cardiovascular disease, and lesser adverse
reactions of either minor or major significance. For example,
the Heart Outcomes Prevention Evaluation HOPE) trial
reported that an angiotensin-converting enzyme inhibitor,
ramipril, reduced fatal and nonfatal cardiovascular events in
high-risk patients, irrespective of whether or not they were
hypertensive [4]. On the other hand, the ‘null’ hypothesis for
treatment of hypertension had been that the benefit of
treatment is entirely related to reduction of arterial pressure
and that the separate actions of the various drug classes are
of no importance [5].
At entry, the baseline characteristics of the doxazosin and
chlorthalidone groups in ALLHAT were similar. Ninety
percent of both groups had been previously treated and were
then changed to their assigned medication. Thereafter, they
were treated similarly with addition of a beta blocker or other
allowed agents (reserpine or clonidine for second step and
Stroke
Chlorthalidone
(%)
6.3
6.3
4.2
3.6*
25.5
21.8**
Congestive heart failure
8.1
4.5**
Coronary revascularization
6.2
5.2***
Combined cardiovascular disease
Results are presented as a percentage of those entered in each arm,
either doxazosin or chlorthalidone. Data from [1]. *P = 0.04, **P <
0.001, ***P = 0.05.
hydralazine for third step) when needed. In both groups,
blood pressure fell significantly from entry levels and
remained lower. Despite a uniform goal of treatment for all
enrolled, a small difference in systolic pressure was found
between the two groups soon after entry and persisted until
the doxazosin arm was discontinued. Overall, the doxazosin
group had a 2–3 mmHg higher systolic pressure during the
trial. Diastolic pressures were equal in the two groups. While
a placebo arm was not included (and would have been
unethical) there is every reason to accept the view that
doxazosin did reduce arterial pressure (i.e. it remains an
antihypertensive drug), but slightly less so than the diuretic.
The difference of 2–3 mmHg in systolic pressure between
the two arms cannot account for doubling of the heart failure
rate by doxazosin, compared to the diuretic as shown in
Table 1. Furthermore, clinicians treating patients in the two
groups were not aware of any difference in response.
Adherence to assigned treatment was 10% higher for
chlorthalidone, compared to doxazosin over 4 years of
observation, but discontinuation of medication was similar for
the two groups (20% for chlorthalidione and 19% for
doxazosin).
Recommended steps
Is doxazosin (or any other alpha receptor blocker) a
dangerous drug? Did the results of ALLHAT reveal drug
toxicity or the ‘lesser charge’ of ineffectiveness? The former
status clearly requires a warning and, in some circumstances,
may lead to withdrawal of approval. The latter requires
widespread information to advise all clinicians who treat
hypertension of better and worse strategies. The available
studies don’t support the concept that doxazosin or alpha
blockers have a direct cardiotoxic effect. Rather, clinical
research implies that, like prazosin, doxazosin has no
sustained hemodynamic benefit for congestive heart failure,
due to development of tolerance (i.e. the lack of a sustained
hemodynamic effect in those with impaired left ventricular
systolic function) [7]. This has led to the suggestion that
emergence of heart failure in the doxazosin cohort of
ALLHAT was the expression of ‘latent’ heart failure at
research
ALLHAT findings regarding doxazosin
Coronary heart disease
Doxazosin
(%)
review
While published guidelines suggest uniform treatment for
hypertension, practice by individual physicians varies
considerably. ALLHAT was conceived and designed to
provide meaningful comparisons of three widely used newer
drug classes to a ‘classic’ diuretic, as given in daily practice
by primary care physicians for treatment of hypertension [6].
The goal of the trial was to assess cardiovascular mortality
and morbidity for stroke, coronary heart disease and
congestive heart failure, as an evidence-based guide for
clinicians who treat hypertension. ALLHAT is a large
multicenter study (44,000 enrolled), with randomization, a
double blind design, nearly complete follow-up of enrolled
subjects, and other features that qualify it as compelling
evidence for clinical decisions.
Event
commentary
Addressing the issues: the rationale for
ALLHAT
Major results of the ALLHAT study
Current Controlled Trials in Cardiovascular Medicine
December 2001 Vol 2 No 6
baseline, or soon thereafter, which either had been kept in
check by previous treatment or was prevented from
appearing by the diuretic or other therapy. The basis for a
diagnosis of heart failure was uniform between the two
groups [8]. The case-fatality rates for heart failure, however,
were also similar for the arms receiving doxazosin or
chlorthalidone; once heart failure appeared, its
consequences were disastrous. In other words, heart failure
as an endpoint in ALLHAT was an important clinical event.
Clinicians who treat hypertension should be aware that
doxazosin, certainly as monotherapy, may be ineffective,
perhaps little better than a placebo, for patients at higher risk
for heart failure. The greater adherence rate for
chlorthalidone compared to doxazosin should not be
overlooked, as well. In a double blind trial, such a pattern
implies that the alpha blocker was, for unknown reasons, less
acceptable that the diuretic alternative. This is new and
important information from a very large trial, that is not likely
to be replicated.
The FDA panel heard the opposing viewpoints on a warning
for doxazosin as a result of the ALLHAT trial. They concluded
that something should be done, but could not take any
further action and, instead, asked for additional analyses. This
may be all that current FDA policies allow. There is, however,
a compelling mandate emerging from those who see the
need for greater safety in the provision of healthcare.
Beneficial therapy should be achieved for as many
hypertensive patients as possible. If even a small fraction of
this large population is given a drug that fails to prevent heart
failure, when effective medication might have been
prescribed, our system of heathcare is just as deficient as if a
more dramatic toxic adverse reaction (such as severe hepatic
reactions to troglitizone) had occurred. Results of large and
well-conducted clinical trials, such as ALLHAT, must be the
basis for optimal healthcare policy.
Competing interests
None declared
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Krakoff
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